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Title: Distinct conformations, aggregation and neuronal internalisation of different tau strains
Author: Karikari, Thomas K.
ISNI:       0000 0004 7224 0003
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2017
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A shared property of several neurodegenerative diseases is the neuronal accumulation of aggregated tau protein. These include Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Many studies have suggested that aggregated tau accumulation in AD brains involves: (i) internalisation of extracellular tau (aggregated or not) into neurons; (ii) induction of endogenous tau aggregation by the internalised tau; and (iii) secretion of part or whole of this aggregated tau complex. This complex then initiates a new cycle of internalisation, aggregation and secretion. While this AD mechanism has strong evidential support, it is unclear if it applies to FTD. It was therefore investigated if and how two FTD-associated tau mutations, V337M and N279K, affect in vitro wild type (WT) tau aggregation and conformation, and studied the cell biological effects of their respective extracellular oligomers. A library of 43 plasmids for expressing full-length and truncated tau and their FTD variants were created, in conjunction with the establishment of a new high-yield tau purification method. Consequently, in vitro biochemical assays showed that the FTD variants distinctively altered the immunological reactivity, the stages of aggregation, and the structural phenotypes of aggregated WT tau four-repeat domain, K18. Internalisation of WT and FTD tau K18 extracellular oligomers was significantly different in human neuroblastoma cells and human stem-cell derived neurons. Internalisation seemed to occur by endocytosis, and the internalised oligomers localised to the nucleus and cytoplasm of human neuroblastoma cells and the soma and neurites of stem cell-derived neurons. Moreover, internalised oligomers co-localised with endogenous tau and the nuclear protein nucleolin, without inducing cell death. These findings provide new perspectives to the cell-to-cell propagation theory of aggregated tau, by demonstrating that cellular internalisation of tau variants may be tightly regulated by the given protein’s folding and aggregation characteristics. This may help to explain several enigmatic aspects of the molecular pathogenesis found in different tauopathies.
Supervisor: Not available Sponsor: Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC Internal medicine